DE1935879C3 - Process for the production of a pharmaceutical lithium preparation - Google Patents

Description

2. The method according to claim 1, characterized in that the ester mixture in an amount of 51 to 61 parts by weight per 100 parts by weight of the lithium is used.

The present invention relates to pharmaceutical preparations, in particular to preparations that ensure sustained delivery of a drug into the bloodstream for a desired period of time.

From DE-PS 5 57 608 preparations are known which contain a mixture of fatty acids. Free fatty acids react with lithium carbonate under the high pressure conditions during tablet production. The described Use of beeswax to achieve a depot effect has the disadvantage that Beeswax is insoluble in water and hardly soluble in alcohol, so that it can be used in the manufacture of tablets badly suited.

In DE-AS 12 58 025 is to achieve a Long-term effect in tablets, the embedding of the active ingredient in fats or waxes suggested. the However, the active ingredient in these tablets was released too quickly and to an inadequate extent.

From the GDR patent 38 396 is the use of a mixture of carboxylic acid ester and one Polyoxyethylene glycol ester (M 6 2000-6000) known. In this way tablets are obtained which initially show a strong release of the active ingredient, which then decreases. The release of the active ingredient takes place within 4 to 12 hours; an even longer duration of action would be beneficial.

The use of a mixture of fatty acid glyceryl esters as a binder in the manufacture of Tablets are known from "Actar Helvet.", 41 (1966), pp. 530-550. As binders, these are glyceryl esters mixed with the active ingredient in the tablet and the tablet disintegrates in the intestinal tract, so that the Fatty acid glyceryl esters no retardation of the effect

cause substance release.

From DE-PS 10 01 456 are absorption-retarding Means known, which from fatty acids, their esters or fatty alcohols and optionally edible wax

sen exist. However, free fatty acids are not suitable as a coating for lithium carbonate, since they are among the High pressure conditions in tablet production react with the active ingredient. Waxes are due less suitable because of their lack of solubility in water and alcohol.

The use of lithium salts in the treatment of manic conditions, especially for Prophylaxis for recurring manic-depressive or depressive illnesses has been for several

^{Known for 5} years Unfortunately, lithium is quickly absorbed and excreted, so that the salt normally has to be administered three to four times a day in order to maintain a therapeutically effective blood level. This is not only cumbersome but also dangerous because lithium tends to build up in the body and produce serious side effects at blood levels only slightly above the therapeutic level. Cases of serious lithium poisoning have been frequently reported. The object of the present invention is therefore to provide a therapeutic preparation containing lithium which only needs to be taken once a day and which maintains a therapeutic blood level of lithium for 24 hours

The invention relates to a method for Manufacture of a pharmaceutical lithium preparation with sustained effectiveness characterized by that the following procedural steps follow one another:

a) mixing dry powdered lithium carbonate fi with dry powdered mannitol,

b) Mixing a solution of a mixture of glycerol mono-. di- and tri-esters of palmitic stearic acid the composition: stearic acid 46.5% by weight, palmitic acid 51% by weight, lauric acid

■ to re 2% by weight and traces of myristic and Oleic acid, monoesters at 12-17% by weight. Di-ester to 43-47% by weight and triester to 35-44% by weight and less than 1% free glycerine in the Ester mixture are present,

c) adding an aqueous solution of acacia gum and kneading the mixture,

d) drying and granulating the mass,

e) pressing into tablets.

The ester mixture is preferably in an amount of 51 to 61 parts by weight per 100 parts by weight therapeutically effective lithium carbonate present. The tabletting auxiliaries are the bulking agent mannitol, the Acacia gum binders and magnesium stearate can be used as a lubricant.

Before the pelletizing, the granules of stage d) are given a lubricant in the form of magnesium stearate admitted. It is added in alcoholic solution and at elevated temperature, the Mixture of powdered medicament and filler

M) is preheated to this temperature before adding the solution during stage b). After adding the binder and kneading the mixture, drying is carried out.

The ester mixture as a delivery means is defined as above.

For further explanation, a special embodiment of the invention is based on the following Example described in more detail.

19 35 1879

Realization example

Contrasted release lithium carbonate tablets are made with the following components:

100 parts by weight of lithium carbonate
16.5 parts by weight of mannitol
9.75 parts by weight of ester mixture
10 parts by weight acacia gum
1.25 parts by weight magnesium stearate

The ester mixture consists of glycerol mono-, di- and tripalmitic stearic ester. It was made from palmitic stearic acid made with the following approximate composition in weight percent.

Stearic acid 463%, palmitic acid 51%,

Lauric acid 2% and

Traces of myristic and oleic acids.

The final ester preparation has the following composition in% by weight: monoester 12-17%, di-ester 43_47q / v and Triester 35-44%, with less than 1% free glycerin is present.

The tablets are prepared in the following way: the mannitol is passed through a sieve (25 mesh, according to the Norm AFNOR = Association Franpaise de Normalization) sieved. The sieved mannitol is in one up container heated to approx. 68 ° C with powdered lithium carbonate of pharmaceutical quality (BPC-1949) mixed.

An alcoholic solution of the ester mixture is made by adding 39 g of it in each 170 ml of alcohol (96 °) and the temperature of the solution is brought to 70 ° C. The solution is then to the powdered mixture of mannitol and lithium carbonate poured at 68 ° C and mixed. An aqueous one Solution of acacia gum is made up with 1 part by weight of acacia gum to 2 parts by volume of water poured the mixture and knead the whole mass. The mass is then at 40 ° C by evaporation dried, ζ B. in an aeromatic drying device. Then it is placed on a No.: 0 sieve (Mesh size 2 mm, wire diameter 0.7 mm) granulated and dried for a further 5 minutes. the dry mass is then further on a No. 16 sieve (sieve size 1.19 mm, wire diameter 0.5 mm) granulated. The magnesium stearate is added to the dry granulate and mixed. The mix will then in a rotary device with flat, cup-shaped and rod-shaped punches Compressed tablets. Each tablet should have a weight of about 550 mg and about 400 mg of lithium carbonate and 39 rrg Estermischur.g contain.

These tablets only need to be administered once a day to be able to achieve therapeutic lithium levels in d> in blood plasma over a period of 24 Hours to keep up. Your effectiveness will be through the following experiments which were carried out with these tablets are documented.

Comparative experiment

A single daily dose of an Iu lithium preparation was administered at 12 noon. the single dose was 1200 and 800 mg, respectively. Curves (1) to (5) show that both Single dose of 1200 mg as well as 800 mg or 1000 mg a constant blood level between 0.6 and 1.6 meq can be maintained, at the dose of 1200 mg even between 0.6 and 1.4 meq. if even for reasons of space, only one daily curve was recorded at a time, it follows from the Curve progression, as well as from the same values at the beginning and end of the curves, that the curves adhere to repeat on consecutive days. In addition, for a patient, such as the cure \ in (2) and (3) show that the measurements were repeated on days further apart with only insignificant deviations.

The curves (1) to (7) relate to a tablet according to the invention.

Curves (9) and (10) show the blood level when a commercial product made from tablets is administered which contain 250 mg lithium carbonai. They are normal tablets with no delayed release of active ingredient. To maintain an effective blood level, 3 daily doses of 500 mg each are required for this preparation required (indicated by the arrows in the graphic representation).

The inadequate blood level when only a single daily dose of conventional Üthiumcarbonatabletten is given and so-called Duretter tablets show curves (6) to (8). Scell the Duretter tablets a long-term preparation with a plastic base. They are the same as in "Modern Medicines" (1972) ! described lithium preparation (»lithium duriles«) comparable.

The administered standard lithium tablets contain

* "> th 300 mg per tablet, the Duretter tablets 330 mg per tablet. It can be seen that the curve of the blood level values obtained with the Duretter tablets - even if somewhat improved - is in principle the same as that of the tablets without delayed release of the active ingredient In particular it can be stated that in each of the corresponding test experiments the blood level has fallen below the limit of 0.6 meq.

For this purpose 10 sheets of drawings

Claims (1)

Patent claims: 1. Process for the production of a pharmaceutical lithium preparation with lasting effectiveness, characterized in that the following process steps follow one another: a) Mixing dry powdered lithium carbonate with dry powdered mannitol, b) Mixing in a solution of a mixture of glycerol mono-, di- and tri-esters of palmitic stearic acid the composition: stearic acid 46.5% by weight, palmitic acid 51% by weight, Lauric acid 2 wt .-% and traces of myristic and oleic acid, with monoesters too 12-17 wt%, diesters 43-47 wt%, and triesters 35-44 wt% and less than 1% solid glycerine in the ester mixture are present. c) Adding an aqueous solution of acacia gum and kneading the mixture. d) drying and granulating the mass. e) pressing into tablets.